1. Field of the Invention
The present invention refers to the use in the prevention and/or treatment of neurodegenerative diseases, such as, for example, Huntington's chorea, Alzheimer's disease, dementia caused by aquired immunodeficiency syndrome (AIDS), infarctual dementia, cerebral ischemia, cerebral hypoxia, Parkinson's disease, epilepsy, head and spinal cord injury, amyotrophic lateral sclerosis, glaucoma/retinopathy, infections and inflammations of the brain, of N-substituted-2-amino-4-phenyl-4-oxo-butanoic acid derivatives which act as inhibitors of kynurenine-3-hydroxylase (KYN-3-OHase), the enzyme which forms part of the metabolic pathway of kynurenine.
A second object of this invention is directed to a restricted class of the above N-substituted-2-amino-4-oxo-4-phenyl-butanoic acid derivatives as novel compounds, either as single enantiomers or as mixture of enantiomers, to their pharmaceutically acceptable salts, to a process for their preparation, and to pharmaceutical compositions containing them.
2. Description of the Background
In the central nervous system (CNS) the metabolism of tryptophan is well known to result largely in the production of indolamines such as the neurotransmitter serotonin, while in the periphery most of non-peptide tryptophan utilisation is along the kynurenine pathway, ultimately leading to the formation of nicotinamide adenine dinucleotide (NAD) (FIG. 1). The legend to FIG. 1 is to be found on the last page of the experimental part. In the last decade several lines of evidence have demonstrated that two intermediates of the kynurenine metabolism, quinolinic acid (QUIN) and kynurenic acid (KYNA), when injected in the CNS, act as a neurotoxin and as a neuroprotectant, respectively. Consequently, the demonstration that these two metabolites of the kynurenine pathway (unable to cross the blood brain barrier), are normal constituents of the mammalian brain, has suggested the existence of this pathway within the CNS and proposed the involvement of QUIN and KYNA in brain physiology and pathology (Stone T. W., Pharmacol. Rew., (1993), 310-379). Both QUIN and KYNA are able to interact with the ionotropic excitatory amino acid receptors. In particular, QUIN is a highly selective agonist at N-methyl-D-aspartate (NMDA) receptor (Stone T. W., Eur. J. Pharmacol., 72, (1981) 411-412), whereas KYNA is a broad spectrum antagonist of the ionotropic excitatory aminoacid receptors, preferentially acting at the glycine co-agonist site of the NMDA receptor (J. Neurochem., 52, (1989) 1319-1328). In vitro studies have demonstrated that the exposure of neuronal cell cultures to relatively low QUIN concentrations are neurotoxic either when applied over a prolonged period of time or in combination with glutamate (Schurr A., Brain Res., 568, (1991) 199-204). In vivo QUIN has been shown to produce convulsions and axon sparing lesions that mimic the nerve cell loss described in human neurodegenerative disorders (Schwarcz R., Science, 219, (1983) 316-318). Moreover an increase in QUIN production has been demonstrated in post-ischemic gerbil brain (Saito K., J. Neurochem., 60, (1993) 180-192), following spinal cord trauma in rats (Stokes B. T., Brain Res., 633, (1994) 348-352) and in guinea pig (Blight A. R., Brain Res., 632, (1993) 314-316), and, finally, in a model of experimental allergic encephalomyelitis (Flagan E. M., J. Neurochem., 64, (1995) 1192-1196). On the other hand, KYNA has shown anticonvulsant and neuroprotective properties in several animal models (Stone T. W. Pharmacol.Rev.45,(1993) 309-379), and, additionally, the experimentally-evoked rise of KYNA concentrations is capable to elicit neuroprotection and seizures reduction (Nozaki K., J. Cereb. Blood Flow Metab., (1992), 12, 400-407; Russi P., J. Neurochem., 59, (1992) 2076). Notably, KYNA when co-injected with QUIN is able to prevent the excitotoxic neuronal damage evoked by the neurotoxin (Foster A. C., Neurosci. Lett., 48, (1984) 273-278). These data taken together suggest that KYNA may act as the brain's own defence against detrimental events, such as excitotoxicity and seizures, leading to pathological situations (Schwarcz R., Neurotoxin and neurodegenerative disease, Ann. N.Y.Sci., 140, vol. 648, 1992). It follows that pharmacological interventions aimed at increasing KYNA formation and/or blocking QUIN synthesis can be useful in the treatment of excitotoxic brain diseases. In the Kynurenine pathway (see FIG. 1), KYN-3-OHase is the first enzyme involved in the formation of QUIN from kynurenine. Pharmacological agents acting as inhibitors of this enzyme able to block the metabolism toward QUIN and, at the same time, to increase KYNA formation, can be useful as neuroprotective agents in the prevention and/or treatment of all the neurodegenerative pathologies involving quinolinic acid or excessive activation of neurotransmission mediated by excitatory amino acid (EAA) receptors.
There is therefore a need to find pharmacological substances which can be useful as neuroprotective agents by means of their activity as inhibitors of the enzyme KYN-3-OHase. The present invention fulfills such a need.